US20090298817A1 - Anti-amnesic compounds and pharmaceutical compositions comprising them - Google Patents

Anti-amnesic compounds and pharmaceutical compositions comprising them Download PDF

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US20090298817A1
US20090298817A1 US12/436,257 US43625709A US2009298817A1 US 20090298817 A1 US20090298817 A1 US 20090298817A1 US 43625709 A US43625709 A US 43625709A US 2009298817 A1 US2009298817 A1 US 2009298817A1
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carbon atoms
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atom
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Marc Verleye
Marie-Emmanuelle Le Guern
Jean-Marie Gillardin
Bernard Hublot
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Biocodex SAS
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Assigned to BIOCODEX reassignment BIOCODEX ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GILLARDIN, JEAN-MARIE, HUBLOT, BERNARD, LE GUERN, MARIE-EMMANUELLE, VERLEYE, MARC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the use of novel anti-amnesic compounds in connection with the prevention or treatment of memory disorders.
  • the etiology of memory disorders is particularly varied.
  • the most common pathologies which involve a memory disorder include dementias, such as Alzheimer's disease, cerebral traumas, cerebral infections, such as encephalitis or meningitis, as well as cerebrovascular, ischemic or hemorrhagic strokes.
  • dementias such as Alzheimer's disease, cerebral traumas, cerebral infections, such as encephalitis or meningitis, as well as cerebrovascular, ischemic or hemorrhagic strokes.
  • the memory disorder may be linked to a biochemical deficiency, as in the case of Wernicke-Korsakov syndrome which is due to a serious vitamin B deficiency caused by chronic alcoholism.
  • the memory disorder may also be of iatrogenic origin, and may in particular be induced by particular narcotic and/or pharmacologically active substances, such as sedatives, benzodiazepines, and related substances used as soporifics, antinauseants and anti-vertigo agents, because of the neuroleptic action thereof, anticholinergic antidepressants, centrally acting antihypertensives, or beta-blockers which cross the hematoencephalic barrier.
  • narcotic and/or pharmacologically active substances such as sedatives, benzodiazepines, and related substances used as soporifics, antinauseants and anti-vertigo agents, because of the neuroleptic action thereof, anticholinergic antidepressants, centrally acting antihypertensives, or beta-blockers which cross the hematoencephalic barrier.
  • Memory disorders encompass in particular the various types of amnesia.
  • amnesia The most common is anterograde amnesia, characterized by an inability to store, retain or recall new knowledge after the event triggering the amnesia. This type of amnesia is observed in particular in patients suffering from dementia or Alzheimer's disease.
  • Retrograde amnesia involves the loss of memories acquired before the onset of the disorder. It is often observed after cerebral trauma.
  • transient global amnesia is a temporary total loss of memory, with an inability to form new memories accompanied by a moderate loss of past memories.
  • This rare variant which regresses spontaneously, is observed primarily in the elderly but may also be caused by migraines, vascular strokes to the temporal lobe, or transient ischemic attacks.
  • the possible treatments for memory disorders generally depend on the cause of the disorder.
  • memory disorders caused by Alzheimer's disease may be partially reduced using donepezil and drugs which improve the brain's cholinergic function.
  • donepezil and drugs which improve the brain's cholinergic function.
  • Two international applications also mention the development of peptides or polypeptides which are effective in treating memory disorders linked to Alzheimer's disease, either by acting on the amnesic effects of the ⁇ -amyloid protein (WO 1995/008999) or by acting as agonists to G protein receptors (WO 1996/039439).
  • the present invention relates to the provision of pharmaceutical compositions which can be used for the prevention or treatment of the various types of memory disorder.
  • Etifoxine or 6-chloro-2-ethylamino-4-methyl-4-phenyl-4H-[3,1]benzoxazine hydrochloride, belongs to the benzoxazine family. It promotes gabaergic transmission by bonding to the site of the chloride channel coupled to the GABA(A) receptor, and is currently used as an anxiolytic. There are few undesirable effects reported subsequent to the use thereof.
  • the present invention is based on the finding, by the inventors, that etifoxine exhibits anti-amnesic action in animals in a model where memory disorder is induced by scopolamine.
  • the present invention thus relates to the use of at least one compound of formula (I) as follows:
  • the present invention also relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, as a drug for the prevention or treatment of memory disorders.
  • the present invention also relates to a method for the prevention or treatment of memory disorder in an individual, comprising the administration to the individual of at least one compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in particular in a prophylactically or therapeutically effective amount.
  • the compound of formula (I) is associated with at least one additional compound for the prevention or treatment of a pathology associated with or giving rise to a memory disorder.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as an active substance:
  • the present invention also relates to products containing:
  • the invention also encompasses the optically active forms of the compound of formula (I) according to the invention, such as the following enantiomers (where R 5 and R 6 are different):
  • the compound of formula (I) according to the invention is the compound of formula (VIII) as follows:
  • the invention also encompasses the optically active forms of the compound of formula (VIII) according to the invention, such as the following enantiomers:
  • the compound of formula (I) or (VIII) according to the invention is the compound of formula (II) as follows:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are as defined above.
  • the invention also encompasses the optically active forms of the compound of formula (II), such as the following enantiomers (where R 5 and R 6 are different):
  • the compound of formula (I), (II) or (VIII), according to the invention is particularly preferably represented by the compound of formula (III) or (IV) as follows:
  • the compound of formula (III) is etifoxine, or 6-chloro-2-ethylamino-4-methyl-4-phenyl-4H-[3,1]benzoxazine hydrochloride.
  • the compound of formula (IV), desethyl etifoxine or 2-amino-6-chloro-4-methyl-4-phenyl-4H-[3,1]benzoxazine, is a metabolite of etifoxine.
  • the invention also encompasses the optically active forms of the compound of formula (III) according to the invention, such as the following enantiomers:
  • the compound of formula (I) or (VIII), according to the invention is the compound of formula (V) as follows:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above.
  • the invention also encompasses the optically active forms of the compound of formula (V) according to the invention, such as the following enantiomers (where R 5 and R 6 are different):
  • the compound of formula (I), (V) or (VIII), according to the invention is particularly preferably represented by the compound of formula (VI) or (VII) as follows:
  • the invention also encompasses the optically active forms of the compound of formula (VI), such as the following enantiomers:
  • An individual is said to be suffering from a “memory disorder” if he has a deficit in his ability to learn new information or an inability to remember information learnt or events which took place before the onset of the disorder.
  • Memory disorders are in particular defined on pages 123 to 163 of the reference manual “ Diagnostic and Statistical Manual IV ” (DSM IV) in relation to the pathologies of delirium, dementias and amnesic disorders.
  • DSM IV Diagnostic and Statistical Manual IV
  • Amnesic disorders which are therefore a subset of memory disorders, are in particular characterized by a deterioration of the memory without any other significant cognitive deteriorations.
  • the classification thereof is based on the suspected etiology, as these disorders may be caused by a general medical affliction, be induced by a substance, or be non-specific.
  • memory disorders are in the present case to be understood as comprising all forms of amnesia, in particular anterograde amnesia, retrograde amnesia, transient global amnesia, amnesic stroke or even pure amnesic syndrome.
  • the memory disorders according to the invention may in particular be due to the action of exogenous substances (i.e. the memory disorder is of iatrogenic origin) or be due to organic lesions. These lesions may in particular be of a degenerative, ischemic, hemorrhagic or traumatic type or be due to deficiencies, for example of vitamins.
  • the non-demential etiology of memory disorders is summarized in particular by Michel & Sellal (2006) Le Concours Médical 128:487-491.
  • the memory disorders are preferentially linked to or caused by the pathologies selected from the list consisting of:
  • the memory disorders are iatrogenic memory disorders, in particular due to the administration of pharmacological compounds such as sedatives, benzodiazepines and related substances, antinauseants and anti-vertigo agents, anticholinergic antidepressants, centrally acting antihypertensives, corticosteroids or beta-blockers which cross the hematoencephalic barrier.
  • pharmacological compounds such as sedatives, benzodiazepines and related substances, antinauseants and anti-vertigo agents, anticholinergic antidepressants, centrally acting antihypertensives, corticosteroids or beta-blockers which cross the hematoencephalic barrier.
  • the additional compound is not a compound of formula (I) according to the invention.
  • the additional compound is for the treatment of a pathology linked to or caused by a memory disorder selected from the list consisting of:
  • the additional compound defined above is preferably selected from the list comprising or consisting of:
  • the drug, pharmaceutical composition or product according to the invention comprises a single dose of approximately 25 mg to approximately 2500 mg, in particular approximately 100 to 1000 mg of the compound of formula (I) as defined above, or the pharmaceutically acceptable salt thereof.
  • the compound of formula (I) as defined above, or the pharmaceutically acceptable salt thereof is administered in a dose of approximately 25 mg/day to approximately 2500 mg/day, in particular approximately 100 mg/day to approximately 1000 mg/day.
  • the drug, pharmaceutical composition or product according to the invention is suitable for oral administration.
  • the drug, pharmaceutical composition or product according to the invention is in the form of a powder, wafers, capsules or sachets.
  • FIG. 1 Histograms representing the mean latency time to enter the dark compartment in the course of information acquisition (hollow bars) or in the course of information retention (hatched bars) as a function of the different treatments performed.
  • Scopolamine (SCOP) or its excipient (dose 0) were administered 30 minutes before acquisition, at a dose of 1.4 mg/kg.
  • Etifoxine (EFX-mg/kg) was administered 35 minutes before acquisition, at the doses indicated.
  • FIG. 2 Histograms representing the mean latency time to enter the dark compartment in the course of information acquisition (hollow bars) or in the course of information retention (hatched bars) as a function of the different treatments performed.
  • Scopolamine (SCOP) or its excipient (dose 0) were administered 30 minutes before acquisition, at a dose of 1.4 mg/kg.
  • Etifoxine (EFX-mg/kg) was administered immediately after acquisition, at the doses indicated.
  • the purpose of the study is to examine the effects of etifoxine on amnesia, induced by a substance which is an antagonist of the cholinergic receptors in rats, scopolamine (see in particular Rush (1988) Behav. Neural. Biol. 1988 50:255-274).
  • Memory capacities are evaluated over the course of the passive avoidance test in a box with two compartments, dark and light.
  • the acquisition step entering the dark compartment is associated with an unpleasant electric shock.
  • the retention step the latency to enter the dark compartment is measured. The lower this latency, the more strongly the animal is suffering from amnesia.
  • Amnesia is induced by administering scopolamine 30 minutes before the information acquisition step.
  • Scopolamine administered 30 minutes before acquisition triggers amnesia in rats, as manifested by the short time period to enter the dark compartment, which is significantly shorter than the time period observed in the reference groups ( FIGS. 1 , 2 ; (SCOP+, EFX 0) vs. (SCOP 0, EFX 0)).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US12/436,257 2008-05-06 2009-05-06 Anti-amnesic compounds and pharmaceutical compositions comprising them Abandoned US20090298817A1 (en)

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FR0853003A FR2930891B1 (fr) 2008-05-06 2008-05-06 Composes anti-amnesiants et compositions pharmaceutiques les comprenant
FR0853003 2008-05-06

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EP (1) EP2116247B1 (fr)
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Publication number Priority date Publication date Assignee Title
FR3051114B1 (fr) * 2016-05-11 2019-09-27 Biocodex Composes pour le traitement de la maladie d'alzheimer

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1745786A (en) * 1929-04-12 1930-02-04 Western Union Telegraph Co Pneumatic dispatch carrier
US3725404A (en) * 1966-11-24 1973-04-03 Hoechst Ag 2-amino-4,4-di-substituted-4h-3,1-benzoxazines
US6379666B1 (en) * 1999-02-24 2002-04-30 Edward L. Tobinick TNF inhibitors for the treatment of neurological, retinal and muscular disorders
US20060293350A1 (en) * 2005-06-27 2006-12-28 Alexander Alanine 8-Alkoxy or cycloalkoxy-4-methyl-3,4-dihydro-quinazolin-2-ylamines
US20070000393A1 (en) * 2004-11-10 2007-01-04 Lam Raymond H Electric grill
US20070109288A1 (en) * 2003-07-09 2007-05-17 Sony Corporation Flat display apparatus and integrated circuit
US20070167446A1 (en) * 2005-07-19 2007-07-19 Marc Verleye Neuroprotective compounds and pharmaceutical compositions comprising them
US20080038331A1 (en) * 2006-03-20 2008-02-14 David Putman Enantiomerically pure S-etifoxine, pharmaceutical compositions thereof and methods of their use

Family Cites Families (4)

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US5470951A (en) 1993-09-29 1995-11-28 City Of Hope Peptides for antagonizing the effects of amyloid βprotein
JPH11506921A (ja) 1995-06-06 1999-06-22 ヒューマン・ジェノム・サイエンシズ・インコーポレイテッド ヒトｇ−タンパク質受容体ｈｃｅｇｈ４５
DE10119862A1 (de) 2001-04-24 2002-11-07 Hf Arzneimittelforsch Gmbh Verwendung von Galanthamin zur Behandlung von Krankheitserscheinungen des zentralen Nervensystems aufgrund von Intoxikationen mit psychotropen Substanzen
US20080039453A1 (en) * 2006-03-20 2008-02-14 David Putman Enantiomerically pure R-etifoxine, pharmaceutical compositions thereof and methods of their use

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1745786A (en) * 1929-04-12 1930-02-04 Western Union Telegraph Co Pneumatic dispatch carrier
US3725404A (en) * 1966-11-24 1973-04-03 Hoechst Ag 2-amino-4,4-di-substituted-4h-3,1-benzoxazines
US6379666B1 (en) * 1999-02-24 2002-04-30 Edward L. Tobinick TNF inhibitors for the treatment of neurological, retinal and muscular disorders
US20070109288A1 (en) * 2003-07-09 2007-05-17 Sony Corporation Flat display apparatus and integrated circuit
US20070000393A1 (en) * 2004-11-10 2007-01-04 Lam Raymond H Electric grill
US20060293350A1 (en) * 2005-06-27 2006-12-28 Alexander Alanine 8-Alkoxy or cycloalkoxy-4-methyl-3,4-dihydro-quinazolin-2-ylamines
US20070167446A1 (en) * 2005-07-19 2007-07-19 Marc Verleye Neuroprotective compounds and pharmaceutical compositions comprising them
US20080038331A1 (en) * 2006-03-20 2008-02-14 David Putman Enantiomerically pure S-etifoxine, pharmaceutical compositions thereof and methods of their use

Non-Patent Citations (4)

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Title
Corsico et al. Psychopharmacologia (Berl.), 45, pages 301-303, 1976. *
Krivanek et al. Inflammation Research, November 1969, Volume 1, Issue 2, pages 36-42. *
Nabeshima et al. 1991, The Journal of Pharmacology and Experimental Therapeutics, Volume 257, No. 1, pages 271-275. *
Schlichter et al. 2000, Neuropharmacology, Volume 39, pages 1523-1535. *

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FR2930891A1 (fr) 2009-11-13
EP2116247B1 (fr) 2015-03-04
FR2930891B1 (fr) 2010-09-24
ES2537792T3 (es) 2015-06-12
EP2116247A3 (fr) 2010-01-06
EP2116247A2 (fr) 2009-11-11

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